Without limiting the scope of the invention, its background is described in connection with the preparation of ifosfamide preparations for use in human therapy.
Heretofore, in this field, the preparation and long term storage of labile hygroscopic compounds, such as ifosfamide, has been difficult. Ifosfamide is a chemotherapeutic agent chemically related to the nitrogen mustards and synthetic analogs of cyclophosphamide. Ifosfamide is 3-(2-chloroethyl)-2-[(chloroethyl amino)] tetrahydro-2H-1, 3, 2-oxazaphosphorin 2-oxide, and has a molecular formula of C.sub.7 H.sub.15 Cl.sub.2 N.sub.2 O.sub.2 P and its molecular weight is 261.1 Daltons.
When first synthesized, ifosfamide is a white crystalline powder that is somewhat soluble in water, however, as the composition is stored, it tends to change to a yellowish color. Ifosfamide belongs to a group of chemical compounds denoted oxazaphosphorins, which are presently in use as therapeutic agents for the treatment of tumors. In particular, ifosfamide is presently used in combination with certain other antineoplastic agents, and is a third line chemotherapeutic for the treatment of testicular cancers derived from germ cells. Generally, it is used in conjunction with a hemorrhagic prophylactic agent, such as mesna.
The lack of stability in water, and its hygroscopic nature, have proven practical challenges to the preparation, processing and long term storage of ifosfamide and its derivatives. In particular, problems with the accuracy of the amount dispensed occur when ifosfamide is prepared for storage as a dried powder. For example, dispensing the dried powder leads to inaccuracies in the amount dispensed and the dosage of ifosfamide when reconstituted and used for treatment. Dispensing the powdered form of ifosfamide into vials for storage also increases the likelihood that microbial contaminants may be introduced during the filling process.
Furthermore, even in the powdered form, ifosfamide suffers from sensitivity to light and heat. The lack of stability of crystallized and reconstituted forms of ifosfamide greatly affect the dosage accuracy during use. The instability of ifosfamide and other oxazaphosphorins has led to the need to find methods for long term storage of these compounds.
One approach to the problem was described in U.S. Pat. No. 5,204,335, entitled "Ifosfamide Lyophilizate and Process for Its Preparation," issued to Sauerbier, et al. Briefly, a lyophilizate is produced by freezing and drying an aqueous or aqueous/alcoholic (preferably aqueous/ethanolic) solution of ifosfamide and a hexitol. The process disclosed involved the use of a hexitol such as, for example, mannitol, to produce an ifosfamide lyophilizate.